Indazole compounds as CCR1 receptor antagonists

ABSTRACT

Disclosed indazoles compounds that are useful as antagonists of CCR1 activity and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of CCR1 including autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. Also disclosed are pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

FIELD OF THE INVENTION

This invention relates to indazoles that are useful as antagonists ofCCR1 activity and are thus useful for treating a variety of diseases anddisorders that are mediated or sustained through the activity of CCR1including autoimmune diseases, such as rheumatoid arthritis and multiplesclerosis. This invention also relates to pharmaceutical compositionscomprising these compounds, methods of using these compounds in thetreatment of various diseases and disorders, processes for preparingthese compounds and intermediates useful in these processes.

BACKGROUND OF THE INVENTION

Chemotactic Cytokine Receptor 1 (CCR1) belongs to a large family (>20)of chemotactic cytokine (chemokine) receptors that interact withspecific chemokines (>50) to mediate leukocyte trafficking, granuleexocytosis, gene transcription, mitogenic effects and apoptosis.Chemokines are best known for their ability to mediate basal andinflammatory leukocyte trafficking. The binding of at least threechemokines (MIP-1 alpha/CCL3, MCP3/CCL7 and RANTES/CCL5) to CCR1 isresponsible for the trafficking of monocytes, macrophages and TH1 cellsto inflamed tissues of rheumatoid arthritis (RA) and multiple sclerosis(MS) patients (Trebst et al. (2001) American J of Pathology 159 p.1701). Macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophagechemoattractant protein 3 (MCP-3) and regulated on activation, normalT-cell expressed and secreted (RANTES) are all found in the CNS of MSpatients, while MIP-1 alpha and RANTES are found in the CNS in theexperimental autoimmune encephalomyelitis (EAE) model of MS (Review:Gerard and Rollins (2001) Nature Immunology). Macrophages and Th1 cellsin the inflamed synovia of RA patients are also major producers of MIP-1alpha and RANTES, which continuously recruit leukocytes to the synovialtissues of RA patients to propagate chronic inflammation (Volin et al.(1998) Clin. Immunol. Immunopathology; Koch et al. (1994) J. Clin.Investigation; Conlon et al. (1995) Eur. J. Immunology). Antagonizingthe interactions between CCR1 and its chemokine ligands is hypothesizedto block chemotaxis of monocytes, macrophages and Th1 cells to inflamedtissues and thereby ameliorate the chronic inflammation associated withautoimmune diseases such as RA and MS.

Evidence for the role of CCR1 in the development and progression ofchronic inflammation associated with experimental autoimmuneencephalitis (EAE), a model of multiple sclerosis, is based on bothgenetic deletion and small molecule antagonists of CCR1. CCR1 deficientmice were shown to exhibit reduced susceptibility (55% vs. 100%) andreduced severity (1.2 vs. 2.5) of active EAE (Rottman et al. (2000) Eur.J. Immunology). Furthermore, administration of small molecule antagonistof CCR1, with moderate affinity (K_(i)=120 nM) for rat CCR1, was shownto delay the onset and reduce the severity of EAE when administeredintravenously (Liang et al. (2000) J. Biol. Chemistry). Treatment ofmice with antibodies specific for the CCR1 ligand MIP-1 alpha have alsobeen shown to be effective in preventing development of acute andrelapsing EAE by reducing the numbers of T cells and macrophagesrecruited to the CNS (Karpus et al. (1995) J. Immunology; Karpus andKennedy (1997) J. Leukocyte Biology). Thus, at least one CCR1 ligand hasbeen demonstrated to recruit leukocytes to the CNS and propagate chronicinflammation in EAE, providing further in vivo validation for the roleof CCR1 in EAE and MS.

In vivo validation of CCR1 in the development and propagation of chronicinflammation associated with RA is also significant. For example,administration of a CCR1 antagonist in the collagen induced arthritismodel (CIA) in DBA/1 mice has been shown to be effective in reducingsynovial inflammation and joint destruction (Plater-Zyberk et al. (1997)Immunology Letters). Another recent publication described potentantagonists of murine CCR1 that reduced severity (58%) inLPS-accelerated collagen-induced arthritis (CIA), when administeredorally (Biorganic and Medicinal Chemistry Letters (15 (2005) 5160-5164).Published results from a Phase I clinical trial with an oral CCR1antagonist demonstrated a trend toward clinical improvement in theabsence of adverse side effects (Haringman et al. (2003) Ann Rheum.Dis.). One third of the patients achieved a 20% improvement inrheumatoid arthritis signs and symptoms (ACR20) on day 18 and CCR1positive cells were reduced by 70% in the synovia of the treatedpatients, with significant reduction in specific cell types including50% reduction in CD4⁺ T cells, 50% reduction in CD8⁺ T cells and 34%reduction in macrophages.

Studies such as those cited above support a role for CCR1 in MS and RAand provide a therapeutic rationale for the development of CCR1antagonists.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds which block theinteraction of CCR1 and its ligands and are thus useful for treating avariety of diseases and disorders that are mediated or sustained throughthe activity of CCR1 including autoimmune diseases, such as rheumatoidarthritis and multiple sclerosis. This invention also relates topharmaceutical compositions comprising these compounds, methods of usingthese compounds in the treatment of various diseases and disorders,processes for preparing these compounds and intermediates useful inthese processes.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest generic aspect the invention provides compounds of theformula (I)

whereinAr₁ is carbocycle, heteroaryl or heterocycle each optionally substitutedby one to three R_(a);X₁ is a —(CH₂)_(n)— wherein one or more hydrogen atoms can be replacedby R_(a);X₂ is Ar₂, —S(O)_(m)—Ar₂, —S(O)_(m)NR_(e)R_(f) or —S(O)_(m)NH—Ar₂,Ar₂ is carbocycle, heteroaryl or heterocycle each optionally substitutedby one to three R_(b);R₁ is hydrogen, C₁₋₆ alkyl or C₁₋₆alkoxyC₁₋₆alkyl;R₂, R₃ are each independently hydrogen or C₁₋₆ alkyl optionallysubstituted by R_(a);R_(a) is C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkoxycarbonyl, amino, mono- or di-C₁₋₆ alkylamino,C₃₋₆ cycloalkylamino, C₁₋₆ alkylaminocarbonyl, C₁₋₆ acyl, C₁₋₆acylamino, C₁₋₆ dialkylaminocarbonyl, hydroxyl, halogen, cyano, nitro,oxo, R₄—S(O)_(m)—NH—, R₄—NH—S(O)_(m)—, aryl or carboxyl;R_(b) is hydroxyl, carboxyl, halogen, —(CH₂)_(n)—CN, nitro, oxo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, —(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—,R₄—S(O)_(m)—NR_(e)—, R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), heterocyclyl, aryl or heteroaryl,each substituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, aryl or carboxyl;each R_(c), R_(d) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ acyl,C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkylC₁₋₆ alkoxy,C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxycarbonyl or —(CH₂)_(n)—NR_(e)R_(f);each R_(e), R_(f) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl or C₁₋₆ acyl;R₄ is hydrogen, C₁₋₆ alkyl, heterocyclyl, aryl or heteroaryl eachoptionally substituted with C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen, hydroxyl,amino, mono- or di-C₁₋₆ alkylamino, C₁₋₆ alkoxycarbonyl, C₁₋₆ acylamino;R₅ is hydrogen or R_(a);R_(x) is hydrogen or halogen;each n, x are independently 0-3;each m is independently 0-2;or the pharmaceutically acceptable salts thereof.

The compound as described in the embodiment immediately above andwherein

Ar₁ is aryl, thienyl, furanyl, pyranyl, oxazolyl, isoxazolyl, thiazolyl,pyrazolyl, pyrrolyl, imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl or triazinyl each optionally substituted by oneto three R_(a);

X₁ is a —(CH₂)_(n)—;

Ar₂ is aryl, furanyl, pyranyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzimidazolonyl, tetrahydropyranyl, dioxanyl,tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl,imidazolyl, thienyl, thiadiazolyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl, pyridinonyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl,piperidinyl, piperazinyl, purinyl, quinolinyl, dihydro-2H-quinolinyl,isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl,indolyl, isoindolyl, benzofuranyl, benzopyranyl or benzodioxolyl eachoptionally substituted by one to three R_(b);R₁ is hydrogen or C₁₋₄ alkyl;R₂, R₃ are each independently hydrogen or C₁₋₃ alkyl;R_(a) is C₁₋₅ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,amino, C₁₋₅ acyl, C₁₋₅ acylamino, halogen, cyano, nitro, hydroxyl, C₁₋₅alkyl-S(O)_(m)—NH—, C₁₋₅ alkyl-NH—S(O)_(m)— or carboxyl;R_(b) is hydroxyl, carboxyl, halogen, cyano, —CH₂—CN, C₁₋₅ alkyl, C₂₋₅alkynyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,—(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—, R₄—S(O)_(m)—NR_(e)—,R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), phenyl, pyrazolyl, pyrrolyl,imidazolyl, thiadiazolyl, pyridinyl, pyridinonyl, pyrimidinyl,pyridazinyl, pyrazinyl, pyrrolidinyl, piperidinyl or piperazinyl, eachsubstituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, phenyl, naphthyl or carboxyl;R₄ is hydrogen, C₁₋₅ alkyl, phenyl, naphthyl, oxazolyl, isoxazolyl,thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl,thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl,pyridinonyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolidinyl, piperidinyl, piperazinyl or tetrahydropyranyl, eachoptionally substituted with halogen, hydroxyl, C₁₋₅alkyl, C₁₋₅ alkoxy,amino, mono- or di-C₁₋₅ alkylamino, C₁₋₅ alkoxycarbonyl, C₁₋₅ acylamino;R_(x) is hydrogen.

The compound as described in the embodiment immediately above andwherein

Ar₁ is phenyl, naphthyl, thienyl, furanyl, pyranyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinylor pyrazinyl each optionally substituted by one to three R_(a);

Ar₂ is phenyl, naphthyl, benzimidazolyl, benzimidazolonyl,thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl,pyridinonyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl,piperazinyl, indolyl, isoindolyl, benzofuranyl or benzopyranyl eachoptionally substituted by one to three R_(b);R₁ is hydrogen or C₁₋₃ alkyl;R₂, R₃ are each independently hydrogen or C₁₋₃ alkyl;R_(a) is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,halogen, cyano, hydroxyl, C₁₋₅ alkyl-S(O)_(m)—NH—, C₁₋₅alkyl-NH—S(O)_(m)— or carboxyl;R_(b) is hydroxyl, carboxyl, halogen, cyano, —CH₂—CN, C₁₋₅ alkyl, C₂₋₄alkynyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,—(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—, R₄—S(O)_(m)—NR_(e)—,R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), phenyl, pyrazolyl, pyrrolyl,imidazolyl, thiadiazolyl, pyridinyl, pyridinonyl, pyrimidinyl,pyridazinyl, pyrazinyl, pyrrolidinyl, piperidinyl or piperazinyl, eachsubstituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, phenyl, naphthyl or carboxyl;each R_(c), R_(d) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆ acyl,C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkylC₁₋₆ alkoxy,C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxycarbonyl or —(CH₂)_(n)—NR_(e)R_(f);each R_(e), R_(f) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, C₁₋₆ alkoxy, hydroxyC₁₋₆ alkyl or C₁₋₆ acyl;R₄ is hydrogen, C₁₋₅ alkyl, phenyl, naphthyl, oxazolyl, isoxazolyl,thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, thienyl, thiadiazolyl,thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl,pyridinonyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolidinyl, piperidinyl or piperazinyl, each optionally substitutedwith halogen, hydroxyl, C₁₋₅ alkoxy, amino, mono- or di-C₁₋₅ alkylamino,C₁₋₅ alkoxycarbonyl, C₁₋₅ acylamino;R₅ is hydrogen, CN, methyl, —S(O)₂—CH₃.

The compound as described in the embodiment immediately above andwherein

Ar₁ is phenyl, naphthyl, thienyl, furanyl, pyranyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinylor pyrazinyl each optionally substituted by one to three R_(a);

X₁ is a —(CH₂)_(n)—;

X₂ is Ar₂;

Ar₂ is phenyl, naphthyl, benzimidazolyl, benzimidazolonyl, morpholinyl,pyridinyl, pyridinonyl, each optionally substituted by one to two R_(b);

R₁ is hydrogen or C₁₋₃ alkyl;

R₂, R₃ are each independently hydrogen or C₁₋₃ alkyl;

R_(a) is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,halogen, cyano, hydroxyl, C₁₋₅ alkyl-S(O)_(m)—NH—, C₁₋₅alkyl-NH—S(O)_(m)— or carboxyl;

R_(b) is carboxyl, halogen, cyano, —CH₂—CN, C₁₋₄ alkyl, CF₃, C₁₋₄alkoxy, C₁₋₄ alkoxycarbonyl, ethynyl, phenyl, imidazolyl, piperidinyl,piperazinyl,

or R_(b) is

NH₂—S(O)₂—,

NH₂—C(O)—CH₂—,

—N(C₁₋₃ alkyl)₂,

—N(C₁₋₃ alkyl)₂C(O)—C₁₋₃ alkyl,

—C(O)NH—C₁₋₃ alkyl,

—C(O)N(C₁₋₃ alkyl)₂,

—C(O)NH—(CH₂)₁₋₂—O—C₁₋₃alkyl,

—C(O)NH₂,

—S(O)₂—C₁₋₃ alkyl,

—S(O)₂—(CH₂)₁₋₂—C(O)—O—C₁₋₃alkyl,

—S(O)₂—NH—C₁₋₃ alkyl,

—S(O)₂—N(C₁₋₃ alkyl)₂,

—CH₂—S(O)₂—N(C₁₋₃ alkyl)₂,

—S(O)₂NH—(CH₂)₁₋₂—O—C₁₋₃alkyl,

—S(O)₂NH—(CH₂)₁₋₂—N(C₁₋₃alkyl)₂,

—S(O)₂NH—(CH₂)₁₋₂—OH,

—S(O)₂NH—(CH₂)₁₋₂—NHC(O)C₁₋₃alkyl),

—S(O)₂NH-(tetrahydropyran-4-yl),

—S(O)₂NR_(e)(1-C₁₋₃alkylpiperidin-4-yl),

—S(O)₂NH-(4-C₁₋₃alkylpiperazin-1-yl),

—S(O)₂NH-(4-diC₁₋₃alkylaminopiperidin-4-yl),

—S(O)₂-morpholinyl,

—C(O)—O—C₁₋₃ alkyl,

—CH₂—C(O)—O—C₁₋₃ alkyl,

—SCF₃ or

—SCH₃.

The compound as described in the embodiment immediately above andwherein

Ar₁ is

and the combination of

is

The following are representative compounds of the invention which can bemade by the general synthetic schemes, the examples, and known methodsin the art.

TABLE I Observed STRUCTURE Name [M + H]⁺

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide 410.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (naphthalen-1-ylmethyl)-amide 396.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (pyridin-2-ylmethyl)-amide 347.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (pyridin-3-ylmethyl)-amide 347.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (pyridin-4-ylmethyl)-amide 347.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-methoxy-benzylamide 376.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-methoxy-benzylamide 376.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-trifluoromethyl-benzylamide 414.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-sulfamoyl-benzylamide 425.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-bromo- benzylamide425.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-chloro- benzylamide380.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-bromo- benzylamide425.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3,5-dimethoxy-benzylamide 406.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide 432.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-dimethylamino-benzylamide 389.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-methanesulfonyl-benzylamide 424.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (biphenyl-2-ylmethyl)-amide 422.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-bromo- benzylamide425.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-acetylamino-benzylamide 403.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-(acetyl-methyl-amino)-benzylamide 417.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-methanesulfonyl-benzylamide 424.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-cyano- benzylamide371.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-fluoro-2-methanesulfonyl-benzylamide 442.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-chloro-4-methylsulfamoyl-benzylamide 473.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide 374.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [(S)-1-(3-bromo-phenyl)-butyl]-amide 467.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [2-(3-methoxy-phenyl)-ethyl]-amide 390.1

4-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester 404.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-trifluoromethylsulfanyl- benzylamide 446.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [2-(3,5-dimethoxy-phenyl)-ethyl]-amide 420.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [2-(3,4-dimethoxy-phenyl)-ethyl]-amide 420.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-phenyl-ethyl)-amide 360.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3,4-dimethoxy-benzylamide 406.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [(R)-1-(3-trifluoromethyl-phenyl)-ethyl]- amide 428.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [1-(3-trifluoromethyl-phenyl)-ethyl]- amide 428.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-methylsulfanyl-benzylamide 392.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-imidazol-1-yl-benzylamide 412.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-dimethylaminomethyl-benzylamide 403.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-methylsulfanyl-benzylamide 392.2

3-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester 404.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-pyridin-4-yl-ethyl)-amide 361.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-pyridin-3-yl-ethyl)-amide 361.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (3-morpholin-4-yl-propyl)-amide 383.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [2-(morpholine-4-sulfonyl)-ethyl]-amide 433.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (3-dimethylsulfamoyl-propyl)-amide 405.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [3-(morpholine-4-sulfonyl)-propyl]-amide 447.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (4-carbamoyl-cyclohexylmethyl)-amide 395.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-chloro-4-methanesulfonyl-benzylamide 458.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-oxo-2,3-dihydro-1H-benzoimidazol-5- ylmethyl)-amide 402.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-dimethylcarbamoyl-benzylamide 417.2

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl benzylamide 464.4

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid [(R)-1-(3-trifluoromethyl-phenyl)-ethyl]- amide 478.4

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]- amide 478.4

1-p-Tolyl-1H-indazole-4- carboxylic acid 3-trifluoromethyl- benzylamide410.5

1-Phenyl-1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide396.5

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid phenethyl-amide410.4

1-(2-Methoxy-phenyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 426.4

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide 428.3

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid [1-(3-trifluoromethyl-phenyl)-ethyl]- amide 478.3

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid (1-phenyl-ethyl)-amide 410.4

1-o-Tolyl-1H-indazole-4- carboxylic acid 3-trifluoromethyl- benzylamide410.5

1-m-Tolyl-1H-indazole-4- carboxylic acid 3-trifluoromethyl- benzylamide410.5

1-(2-Cyano-phenyl)-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 421.5

1-Pyridin-3-yl-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 397.5

1-Pyridin-2-yl-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 397.5

1-(2-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-trifluoromethyl-benzylamide 414.4

1-(2-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-trifluoromethyl-benzylamide 413.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-trifluoromethyl-benzylamide 414.9

1-Pyridin-4-yl-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 397.5

1-(3,4-Dichloro-phenyl)-1H- indazole-4-carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]- amide 478.4

1-(3,4-Difluoro-benzyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 432.4

1-Thiophen-2-yl-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 402.5

1-Thiophen-3-yl-1H-indazole-4- carboxylic acid 3-trifluoromethyl-benzylamide 402.5

1-(3-Chloro-4-fluoro-benzyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 448.4

1-(2,4-Difluoro-benzyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 431.6

1-(4-Fluoro-2-methyl-benzyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 428.2

1-(6-Fluoro-pyridin-3-yl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 415.4

1-(4-Fluoro-3-methyl-benzyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 428.2

1-(4-Chloro-benzyl)-1H-indazole- 4-carboxylic acid 3-trifluoromethyl-benzylamide 430.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-carbamoyl-pyridin-4-ylmethyl)-amide 390.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-bromo-2-chloro-benzylamide 460.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (4-bromo-2-chloro-benzyl)-methoxymethyl- amide 504.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-chloro-4-cyano-benzylamide 405.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-carbamoyl-2-chloro-benzylamide 423.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-ethynyl-pyridin-3-ylmethyl)-amide 371.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-iodo- benzylamide472.3

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-cyano- benzylamide371.3

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide 377.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-carbamoyl-benzylamide 389.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-fluoro-4-methylsulfamoyl-benzylamide 456.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide 363.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide 377.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-cyano-pyridin-4-ylmethyl)-amide 372.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide 425.4/427.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-methanesulfonyl-pyridin-3- ylmethyl)-amide 426.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-cyano-pyridin-3-ylmethyl)-amide 373.0

4-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid methyl ester 405.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-methylsulfamoyl-benzylamide 439.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (4-methanesulfonyl-benzyl)-propyl- amide 466.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amide 363.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-carbamoylmethyl-6-oxo-1,6- dihydro-pyridin-3-ylmethyl)-amide 420.9

6-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide 517.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (2-chloro-4-dimethylsulfamoyl-benzyl)-methyl- amide 520.5

6-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide 492.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylmethyl)- amide 377.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(morpholine-4-sulfonyl)-benzylamide 496.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-dimethylsulfamoyl-benzylamide 452.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-isopropylsulfamoyl-benzylamide 467.4

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(2-methoxy-ethylsulfamoyl)-benzylamide 483.4

1-(4-Fluoro-phenyl)-6- methanesulfonyl-1H-indazole-4- carboxylic acid4-methylsulfamoyl- benzylamide 516.1

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide 465.0

1-(4-Fluoro-phenyl)-6-methyl-1H- indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide 544.0

[5-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-2-oxo-2H-pyridin-1-yl]- acetic acid ethyl ester 450.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 2-methanesulfonyl-benzylamide 424.7

1-(4-Fluoro-phenyl)-4-(4- methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6- carboxylic acid ethyl ester 511.1

1-(4-Fluoro-phenyl)-4-(4- methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6- carboxylic acid 484.0

[4-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-2-oxo-2H-pyridin-1-yl]- acetic acid ethyl ester 450.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)- amide 378.0

4-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-benzoic acid 390.1

3-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-benzoic acid 390.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-methylsulfamoylmethyl- benzylamide 452.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(isopropylsulfamoyl-methyl)- benzylamide 482.0

1-(4-Fluoro-phenyl)-1H-indazole- 4,6-dicarboxylic acid 6- methylamide4-(4- methylsulfamoyl-benzylamide) 495.2

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (1-cyanomethyl-2-oxo-1,2-dihydro-pyridin-4- ylmethyl)-amide 402.3

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(2-dimethylamino-ethylsulfamoyl)- benzylamide 495.7

1-(4-Fluoro-phenyl)-1H-indazole- 4,6-dicarboxylic acid 6-[(2-hydroxy-ethyl)-amide] 4-(4- methylsulfamoyl-benzylamide) 525.3

5-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic acid ethyl ester 419.9

1-(4-Fluoro-phenyl)-6-[(2- methoxy-ethyl)-methyl-amino]-1H-indazole-4-carboxylic acid 4- methylsulfamoyl-benzylamide 524.1

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-carbamoyl-pyridin-3-ylmethyl)-amide 391.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-methylcarbamoyl-pyridin-3- ylmethyl)-amide 405.0

3-[5-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]- propionic acid methyl ester 498.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-methylcarbamoyl-benzylamide 403.8

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-propylcarbamoyl-benzylamide 431.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-ethylcarbamoyl-benzylamide 417.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-(2-methoxy-ethylcarbamoyl)-benzylamide 447.8

1-(4-Fluoro-phenyl)-6- methylamino-1H-indazole-4- carboxylic acid4-methylsulfamoyl- benzylamide 468.7

5-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-nicotinic acid ethyl ester 419.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (5-methylcarbamoyl-pyridin-3- ylmethyl)-amide 404.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (5-carbamoyl-pyridin-3-ylmethyl)-amide 390.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [6-(3-hydroxy-propane-1-sulfonyl)-pyridin-3- ylmethyl]-amide 469.7

3-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-methanesulfonyl-benzylamide 504.6

3-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide 519.6

6-Dimethylamino-1-(4-fluoro- phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl- benzylamide 482.0

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(2-hydroxy-ethylsulfamoyl)-benzylamide 469.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide 362.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(2-acetylamino-ethylsulfamoyl)-benzylamide 510.8

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(4-methyl-piperazine-1-sulfonyl)-benzylamide 508.8

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(tetrahydro-pyran-4-ylsulfamoyl)-benzylamide 509.8

[4-({[1-(4-Fluoro-phenyl)-1H- indazole-4-carbonyl]-amino}-methyl)-pyridin-2-yloxy]-acetic acid ethyl ester 449.5

1-(4-Fluoro-phenyl)-6-hydroxy-1H- indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide 454.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(1-methyl-piperidin-4-ylsulfamoyl)- benzylamide 522.8

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-[methyl-(1-methyl-piperidin-4-yl)-sulfamoyl]- benzylamide 536.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 4-(4-dimethylamino-piperidine-1- sulfonyl)-benzylamide 536.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-acetylamino-pyridin-3-ylmethyl)-amide 404.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-methanesulfonylamino-pyridin-3- ylmethyl)-amide 440.7

6-(2-Dimethylamino-ethylamino)- 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl- benzylamide 524.8

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 3-methanesulfonyl-benzylamide 449.7

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid (6-bromo-pyridin-3-ylmethyl)-amide 449.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4- ylmethyl]-amide 407.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-methylsulfamoyl-benzylamide 439.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-dimethylsulfamoyl-benzylamide 453.5

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-ethylsulfamoyl-benzylamide 453.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-isopropylsulfamoyl-benzylamide 467.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-(2-methoxy-ethylsulfamoyl)-benzylamide 483.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid 3-(2-acetylamino-ethylsulfamoyl)-benzylamide 510.7

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid (6-methanesulfonylmethyl-pyridin-3- ylmethyl)-amide 439.7

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid (6-methanesulfonyl-pyridin-3- ylmethyl)-amide 449.7

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-(4-methyl-piperazine-1-sulfonyl)- benzylamide 532.8

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid (6-methanesulfonylamino-pyridin-3- ylmethyl)-amide 465.1

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-(1-methyl-piperidin-4-ylsulfamoyl)- benzylamide 547.8

6-Cyano-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid 4-[methyl-(1-methyl-piperidin-4-yl)- sulfamoyl]-benzylamide 560.9

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [1-(6-methanesulfonyl-pyridin-3-yl)- butyl]-amide 467.6

1-(4-Fluoro-phenyl)-1H-indazole- 4-carboxylic acid [(S)-1-(6-methanesulfonyl-pyridin-3-yl)- propyl]-amide 453.6

6-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]- amide M = 532.6

6-Bromo-1-(4-fluoro-phenyl)-1H- indazole-4-carboxylic acid [(S)-1-(6-methanesulfonyl-pyridin-3-yl)- propyl]-amide 530.9/532.7

1-(4-Fluoro-phenyl)-6- methanesulfonyl-1H-indazole-4- carboxylic acid[(S)-1-(6- methanesulfonyl-pyridin-3-yl)- propyl]-amide [M] = 530.7or the pharmaceutically acceptable salts thereof.

For all compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

The invention also relates to pharmaceutical preparations, containing asan active substance one or more compounds of the invention, or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g. ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of the invention can exist in more than onetautomeric form. The invention includes methods using all suchtautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic or non-aromaticring systems. The non-aromatic ring systems may be mono- orpolyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 memberedbicyclic or spirocyclic heterocycle radical which may be eithersaturated or unsaturated. Each heterocycle consists of carbon atoms andone or more, preferably from 1 to 4 heteroatoms chosen from nitrogen,oxygen and sulfur. The heterocycle may be attached by any atom of thecycle, which results in the creation of a stable structure.

The term “heteroaryl” shall be understood to mean an aromatic 5-8membered monocyclic or 8-11 membered bicyclic ring containing 1-4heteroatoms such as N, O and S.

Unless otherwise stated, heterocycles and heteroaryl include but are notlimited to, for example furanyl, pyranyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, tetrahydropyranyl, dioxanyl, tetrahydrofuranyl,oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl,thienyl, thiadiazolyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,pyrrolidinyl, piperidinyl, piperazinyl, purinyl, quinolinyl,dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl,thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl,benzopyranyl and benzodioxolyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in definitions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include its hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “alkyl” refers to a saturated aliphatic radical containing fromone to ten carbon atoms or a mono- or polyunsaturated aliphatichydrocarbon radical containing from two to twelve carbon atoms. Themono- or polyunsaturated aliphatic hydrocarbon radical containing atleast one double or triple bond, respectively. “Alkyl” refers to bothbranched and unbranched alkyl groups. It should be understood that anycombination term using an “alk” or “alkyl” prefix refers to analogsaccording to the above definition of “alkyl”. For example, terms such as“alkoxy”, “alkylthio” refer to alkyl groups linked to a second group viaan oxygen or sulfur atom. “Alkanoyl” refers to an alkyl group linked toa carbonyl group (C═O).

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “halogenated”, “partially or fullyhalogenated”; partially or fully fluorinated; “substituted by one ormore halogen atoms”, includes for example, mono, di or tri haloderivatives on one or more carbon atoms. For alkyl, a nonlimitingexample would be —CH₂CHF₂, —CF₃ etc.

Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogsthereof, described herein shall be understood to be optionally partiallyor fully halogenated.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the invention.

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the invention. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce compounds of theinvention. Simple chemical transformations include hydrolysis, oxidationand reduction. Specifically, when a prodrug is administered to apatient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula I may be made using the general syntheticmethods described below, which also constitute part of the invention.

General Synthetic Methods

The invention additionally provides for methods for making compounds offormula I. The compounds of the invention may be prepared by the generalmethods and examples presented below, and methods known to those ofordinary skill in the art and reported in the chemical literature.Unless otherwise specified, solvents, temperatures, pressures, and otherreaction conditions may be readily selected by one of ordinary skill inthe art. Specific procedures are provided in the Synthetic Examplessection. Intermediate benzyl amines are commercially available, or maybe synthesized via catalytic reduction of the corresponding arylnitriles with Pd/C (Van Rompaey, K. et al, Tetrahedron, 2003, 59 (24),4421) or Raney Ni (Gould, F. et al, J. Org. Chem., 1960, 25, 1658) orthrough displacement of a benzyl bromide with sodium azide and reduction(see example 2 below). Intermediate chiral and racemicaminomethylpyridines may also be commercially available or prepared bymethods known to those skilled in the art. For example, methods ofpreparing 1-substituted-1-pyridylmethylamines from aldehydes or ketonesare known (see, Kuduk, S. D. et al, Tetrahedron Lett., 2004, 45, 6641and Chelucci, G. Tetrahedron: Asymmetry 2006, 17, 3163). Amide bondformations may be carried out by standard coupling conditions well-knownin the art (see, for example, M. Bodanszky, The Practice of PeptideSynthesis (Springer-Verlag: 1984), which is hereby incorporated byreference in its entirety), for example, by reacting a carboxylic acidand an amine in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and1-hydroxybenzotriazole. Reaction progress may be monitored byconventional methods such as thin layer chromatography (TLC).Intermediates and products may be purified by methods known in the art,including column chromatography, HPLC or recrystallization.

The methods described below and in the Synthetic Examples section may beused to prepare the compounds of formula I. In the schemes below, Ar₁,R₁—R₅, X₁ and X₂ shall have the meanings defined in the detaileddescription of formula I.

Compounds of formula I may be prepared as shown in Scheme I.

An indazole-4-carboxylic acid is coupled to the desired amine usingstandard coupling amide conditions, for example by treatment with(benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PyBOP) and triethylamine in a suitable solvent such as DMF. Theresultant indazole-4-carboxamide is then treated with the desired Ar₁I(Ar₁=optionally substituted aryl or heteroaryl) in the presence of CuI,K₂CO₃, and an amine ligand (such as racemictrans-N,N′-dimethylcyclohexane-1,2-diamine) in a suitable solvent suchas DMF to form the compound of formula I.

Another approach that may be used to obtain compounds of formula I isillustrated in Scheme II.

In this method, a 1-substituted-1H-indazole-4-carboxylic acid is treatedwith the desired amine under standard amide coupling conditions, such astreatment with PyBOP, TEA or treatment with HATU to afford the desiredcompound of formula I. Alternatively, the1-substituted-1H-indazole-4-carboxylic may be converted in situ to thecorresponding acid chloride, for example, by treatment with oxalylchloride in dichloromethane or with neat thionyl chloride. The crudeacid chloride was concentrated in vacuo and treated with the desiredamine in the presence of an amine base such as triethylamine (TEA) orN,N-diisopropylethylamine (DIEA) in a suitable solvent such asdichloromethane (DCM) to form the compound of formula I.

Compounds of formula I prepared by the above methods may be furtherconverted to additional compounds of formula I by methods known in theart and exemplified in the Synthetic Examples section below.

SYNTHETIC EXAMPLES Example 1 Synthesis of1-(4-Fluorophenyl)-1H-indazole-4-carboxylic acid3-trifluoromethyl-benzylamide (1)

To a stirred room temperature solution of indazole-4-carboxylic acid(1.0 g, 6.1 mmol) in DMF (15 mL) was added PyBOP (3.5 g, 6.5 mmol) andtriethylamine (0.90 g, 7.5 mmol). After 15 minutes,3-trifluoromethyl-benzylamine (1.2 g, 7.0 mmol) was added. After 4hours, the mixture was quenched with water (30 mL) and diluted withethyl acetate (20 mL). The organic layer was separated, washed withbrine (30 mL), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography eluting with agradient of 20-60% ethyl acetate in hexanes to afford1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide.

A mixture of 1H-indazole-4-carboxylic acid 3-trifluoromethyl-benzylamide(1.1 g, 3.4 mmol), copper(I) iodide (0.005 g, 0.02 mmol), potassiumcarbonate (0.04 g, 0.3 mmol) and 4-fluoroiodobenzene (0.04 g, 0.2 mmol)were charged in a sealed tube at room temperature. The tube wasevacuated and back-filled with argon. The solids were dissolved in DMF(6 mL) and the resultant solution was treated withrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.005 g, 0.04 mmol). Thesolution was stirred at 120° C. for 3 hours and cooled to roomtemperature. The solution was diluted with water (15 mL) and ethylacetate (30 mL). The organic layer was separated, washed with brine anddried over sodium sulfate. The solvent was removed in vacuo. The cruderesidue was purified by silica gel chromatography eluting with agradient of 10-40% ethyl acetate in hexanes to afford the titlecompound.

The following compounds were also prepared by methods described inExample 1:

-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl benzylamide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    [(S)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    [(R)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-p-Tolyl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Phenyl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    phenethyl-amide,-   1-(2-Methoxy-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    [2-(3-fluoro-phenyl)-ethyl]-amide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    [1-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    (1-phenyl-ethyl)-amide,-   1-o-Tolyl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-m-Tolyl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(2-Cyano-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Pyridin-3-yl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Pyridin-2-yl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(2-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(3-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Pyridin-4-yl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(3,4-Dichloro-phenyl)-1H-indazole-4-carboxylic acid    [2-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-(3,4-Difluoro-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Thiophen-2-yl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-Thiophen-3-yl-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(3-Chloro-4-fluoro-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(2,4-Difluoro-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(4-Fluoro-2-methyl-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(6-Fluoro-pyridin-3-yl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide,-   1-(4-Fluoro-3-methyl-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide, and-   1-(4-Chloro-benzyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide.

Example 2 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (2) a)1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid

Indazole-4-carboxylic acid (2.00 g, 12.3 mmol) was suspended in methanol(20 mL) and toluene (30 mL) at room temperature. A solution of 2 Mtrimethylsilyl diazomethane (12 mL, 24 mmol) in toluene was added slowlyand the mixture was stirred at room temperature until the solutionturned yellow. The reaction was quenched with concentrated acetic acid(5 mL) and the solvent was removed in vacuo. The residue was purified bysilica gel chromatography eluting with a gradient of 0-30% ethyl acetatein hexanes to afford 1H-indazole-4-carboxylic acid methyl ester.

A mixture of 1H-indazole-4-carboxylic acid methyl ester (5.0 g, 28mmol), copper(I) iodide (5.7 g, 3.0 mmol), potassium carbonate (4.15 g,30.0 mmol) and 4-fluoroiodobenzene (3.47 g, 30.0 mmol) was charged in asealed tube at room temperature. The tube was evacuated, back-filledwith argon and dimethylformamide (20 mL) was added followed byrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.93 g, 6.5 mmol). Thesolution was stirred at 120° C. for 3 hours. The solution was cooled toroom temperature and diluted with water (50 mL) and ethyl acetate (80mL). The organic layer was separated, washed with brine (30 mL), anddried over sodium sulfate. The crude product was filtered, concentratedand purified by silica gel chromatography eluting with a gradient of0-30% ethyl acetate in hexanes to afford1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.

To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylicacid methyl ester (2.0 g, 7.4 mmol) in water (20 mL) and methanol (20mL) was added a solution of 2 N sodium hydroxide (10 mL). The solutionwas warmed at reflux for 1 hour. The solution was cooled to roomtemperature and acidified with 1 N aqueous HCl (pH=3-4). The white solidwas obtained by filtration, washed with MeOH (30 mL) and dried to afford1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.

b) 4-Aminomethyl-N-methyl-benzenesulfonamide

To a chilled (0° C.) stirred solution of4-(bromomethyl)-benzenesulfonylchloride (3.0 g, 11 mmol) in DCM (100 mL)was added methylamine hydrochloride (1.2 g, 12 mmol). After 30 minutes,water (100 mL) was added. The organic layer was separated, washed withbrine (30 mL), and dried over sodium sulfate and concentrated in vaucoto afford 4-bromomethyl-N-methyl-benzenesulfonamide.

To a stirred room temperature solution of4-bromomethyl-N-methyl-benzenesulfonamide (2.70 g, 10.0 mmol) in DMF (15mL) was added sodium azide (0.90 g, 13 mmol). The mixture was stirred at40° C. for 16 hours. The solution was poured into water (60 mL) anddiluted with ethyl acetate (100 mL). The organic layer was separated andwashed with brine (30 mL), dried over sodium sulfate and concentrated invacuo to afford 4-azidomethyl-N-methyl-benzenesulfonamide.

A mixture of 4-azidomethyl-N-methyl-benzenesulfonamide (2.20 g, 10.0mmol), cyclohexadiene (8.90 mL, 90.0 mmol) and palladium hydroxide (20%on carbon, 1.4 g, 2.0 mmol) in MeOH (20 mL) was warmed at 65° C. for 2hours. The solution was cooled to room temperature and filtered throughdiatomaceous earth. The solvent was removed in vacuo to afford4-aminomethyl-N-methyl-benzenesulfonamide.

c) 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide

To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylicacid (0.05 g, 0.2 mmol) in DMF (10 mL) was added PyBOP (0.14 g, 0.30mmol) and triethylamine (0.07 g, 0.6 mmol) at room temperature. After 15minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.04 g, 0.2 mmol)was added. After 5 hours, the mixture was quenched with water (30 mL)and diluted with ethyl acetate (30 mL). The organic layer was separated,washed with brine (30 mL), dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with a gradient of 0-30% ethyl acetate in hexanes to afford thetitle compound.

The following compounds were also prepared by methods described inExample 2:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-bromo-2-chloro-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-iodo-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-fluoro-4-methylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-cyano-pyridin-4-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-bromo-pyridin-3-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-cyano-pyridin-3-ylmethyl)-amide,-   4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylic    acid methyl ester,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(morpholine-4-sulfonyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-dimethylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-isopropylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(2-methoxy-ethylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-methanesulfonyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methylsulfamoylmethyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(isopropylsulfamoyl-methyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(2-dimethylamino-ethylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(2-acetylamino-ethylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(4-methyl-piperazine-1-sulfonyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(tetrahydro-pyran-4-ylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(1-methyl-piperidin-4-ylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-[methyl-(1-methyl-piperidin-4-yl)-sulfamoyl]-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(4-dimethylamino-piperidine-1-sulfonyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-ethylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-isopropylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-(2-methoxy-ethylsulfamoyl)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-(2-acetylamino-ethylsulfamoyl)-benzylamide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [1-(6-methanesulfonyl-pyridin-3-yl)-butyl]-amide.

Example 3 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(1-naphthalen-1-yl-ethyl)-amide (3)

1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (40.0 mg, 0.156 mmol)and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (89 mg, 0.23 mmol) were combined in a 20 mLvial and dimethylacetamide (DMA) (1 mL) was added. The yellow solutionwas stirred at room temperature for 10 minutes and then a solution of1-(1-napthyl)ethylamine (40.1 mg, 0.234 mmol) and N-methylmorpholine(NMM) (0.086 mL, 0.78 mmol) in DMA (0.20 mL) was added. The mixture wasshaken at room temperature for 16 hours then the solution was evaporatedin vacuo. The crude product was purified by preparative reversed-phaseHPLC to afford the title compound.

The following compounds were also prepared by methods described inExample 3:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-naphthalen-1-yl-ethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (naphthalen-1-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (pyridin-2-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (pyridin-3-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (pyridin-4-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-methoxy-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-methoxy-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-trifluoromethyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-sulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-bromo-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-chloro-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-bromo-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3,5-dimethoxy-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-fluoro-3-trifluoromethyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-dimethylamino-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methanesulfonyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (biphenyl-2-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-bromo-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-acetylamino-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-(acetyl-methyl-amino)-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-methanesulfonyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-cyano-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-fluoro-2-methanesulfonyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-chloro-4-methylsulfamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-methyl-1-phenyl-ethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [(S)-1-(3-bromo-phenyl)-butyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [2-(3-methoxy-phenyl)-ethyl]-amide,-   4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoic    acid methyl ester,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-trifluoromethylsulfanyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [2-(3,5-dimethoxy-phenyl)-ethyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [2-(3,4-dimethoxy-phenyl)-ethyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-phenyl-ethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3,4-dimethoxy-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [(R)-1-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [1-(3-trifluoromethyl-phenyl)-ethyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-methylsulfanyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-imidazol-1-yl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-dimethylaminomethyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methylsulfanyl-benzylamide,-   3-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoic    acid methyl ester,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-pyridin-4-yl-ethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-pyridin-3-yl-ethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (3-morpholin-4-yl-propyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [2-(morpholine-4-sulfonyl)-ethyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (3-dimethylsulfamoyl-propyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [3-(morpholine-4-sulfonyl)-propyl]-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (4-carbamoyl-cyclohexylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    2-chloro-4-methanesulfonyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethyl)-amide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-dimethylcarbamoyl-benzylamide.

Example 4 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-bromo-pyridin-3-ylmethyl)-amide (4)

To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(0.400 g, 1.56 mmol) in CH₂Cl₂ (5 mL) at room temperature was addedoxalyl chloride (0.86 mL, 1.7 mmol) followed by DMF (20 μL). Gasevolution was observed. After 30 minutes, the solution was concentratedin vacuo to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acidchloride which was used without further purification.

A mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid chloride(416 mg, 1.51 mmol), 6-bromo-pyridin-3-yl-methylamine (311 mg, 1.66mmol) and DMAP (18.5 mg, 0.151 mmol) in DCM (10 mL) was treated withDIEA (1.32 mL, 7.56 mmol). The solution was stirred at room temperature.After 16 hours the mixture was diluted with DCM (30 mL). The organiclayer was washed with saturated aqueous NH₄Cl (2×10 mL), saturatedaqueous NaHCO₃ (2×10 mL), water (10 mL), brine (10 mL) and dried overMgSO₄, filtered and concentrated. The residue was purified by silica gelchromatography eluting with a gradient of 0-50% ethyl acetate in hexanesto afford the title compound as a white solid.

The following compounds were also prepared by methods described inExample 4:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-methoxy-pyridin-4-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-methoxy-pyridin-3-ylmethyl)-amide,-   5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-nicotinic    acid ethyl ester,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-methylsulfamoyl-benzylamide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-dimethylsulfamoyl-benzylamide.

Example 5 Synthesis of5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylicacid ethyl ester (5)

In a pressure reactor with stirring, a mixture of the1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-bromo-pyridin-3-ylmethyl)-amide (260 mg, 0.61 mmol), triethylamine(0.17 mL, 1.2 mmol), dichloro(bisbenzonitrile) palladium (4.7 mg, 0.011mmol), and 1,1-bis(diphenylphosphino)ferrocene (dppf) (20.3 mg, 0.0365mmol) in absolute ethanol (10 mL) was charged with 15 bars of carbonmonoxide and warmed at 140° C. After 4 hours, the pressure reactor wasthen cooled to room temperature, chilled on ice and returned toatmospheric pressure. The solution was diluted with saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with saturated aqueous ammoniumchloride (2×25 mL), brine (25 mL), dried over magnesium sulfate,filtered and concentrated. The resulting orange solid was purified bysilica gel chromatography, eluting with a gradient of 0-10% MeOH inCH₂Cl₂. The resulting solid was purified again by silica gelchromatography, eluting with a gradient of 70-100% ethyl acetate inhexanes to afford the title compound.

Example 6 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-carbamoyl-pyridin-3-ylmethyl)-amide (6)

A solution of5-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylicacid ethyl ester (Example 5) (60 mg, 0.1 mmol) in a 7 N solution ofammonia in methanol (0.65 mL, 4.6 mmol) was stirred at 100° C. in asealed tube for 16 hours. The mixture was cooled to room temperature andfiltered. The solid was washed with MeOH (3×3 mL) and dried. The solidwas then triturated with ethyl acetate (2 mL), sonicated, filtered andair dried to afford the title compound.

The following compounds were also prepared by methods described inExample 6:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-methylcarbamoyl-pyridin-3-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (5-carbamoyl-pyridin-3-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (5-methylcarbamoyl-pyridin-3-ylmethyl)-amide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-carbamoyl-pyridin-4-ylmethyl)-amide.

Example 7 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-methanesulfonyl-pyridin-3-ylmethyl)-amide (7)

A microwave tube was charged with1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-bromo-pyridin-3-ylmethyl)-amide (650 mg, 1.5 mmol), copper(II)triflate (550 mg, 1.5 mmol) and sodium methanesulfinate (230 mg, 2.3mmol). The flask was sealed, evacuated and purged (3 times) withnitrogen. The solids were taken up in DMSO (5 mL) andN,N′-dimethylethylene diamine (0.490 mL, 4.59 mmol) was added. Thesolution was stirred at 100° C. After 16 hours, the mixture was dilutedwith EtOAc (10 mL) and washed with saturated aqueous NH₄Cl (5 mL),saturated aqueous NaHCO₃ (5 mL) and brine (5 mL). The organic layer wasdried over MgSO₄, filtered through diatomaceous earth and concentrated.The residue was purified by silica gel chromatography eluting with agradient of 0-80% ethyl acetate in hexanes. Fractions containing theproduct were pooled and further purified by silica gel chromatographyeluting with a gradient of 0-60% ethyl acetate in hexanes. Desiredfractions were pooled and concentrated, and the solid was trituratedwith hexanes (10 mL) to afford the title compound as a white solid.

The following compound was prepared by the methods described in Example7:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [(S)-1-(6-methanesulfonyl-pyridin-3-yl)-propyl]-amide.

The following compound was prepared with modifications to Example 7: 3equivalents of CuI was used as a catalyst instead of copper triflate,and 3 equivalents of sodium 3-methoxy-3-oxopropane-1-sulfinate was usedinstead of sodium methane sulfinate. The solvent was DMSO with no amineligand was added. The mixture was warmed at 110° C. for 30 minutes usingmicrowave heating (as described in Baskin, J. M., et al., TetrahedronLett., 2002, 43 (47), 8479):

-   3-[5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionic    acid methyl ester.

Example 8 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid[6-(3-hydroxy-propane-1-sulfonyl)-pyridin-3-ylmethyl]-amide (8)

The solution of3-[5-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-sulfonyl]-propionicacid methyl ester (33 mg, 0.066 mmol) in THF (5 mL) was treated withlithium borohydride (8.7 mg, 0.40 mmol) at room temperature and themixture was warmed at reflux. After 1 hour, the reaction was cooled toroom temperature, quenched with water (50 mL) and diluted with ethylacetate (50 mL). The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (2×25 mL). The combined organic layerswere washed with brine (20 mL), dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with a gradient of 0-10% MeOH in CH₂Cl₂ to afford the titlecompound.

The following compound was also prepared by methods described in Example8:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-amide.

Example 9 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(4-bromo-2-chloro-benzyl)-methoxymethyl-amide (9)

To a room temperature solution of1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-bromo-2-chloro-benzylamide (1.5 g, 3.3 mmol) in DMF (30 mL) was addeda 60% dispersion of sodium hydride in mineral oil (145 mg, 3.60 mmol).After stirring for 10 minutes, chloromethyl methyl ether (0.28 mL, 3.6mmol) was added. After 16 hours, the mixture was then diluted with water(30 mL) and extracted with ethyl acetate (3×20 mL). The extract waswashed with saturated aqueous ammonium chloride (30 mL) followed bybrine (30 mL) and dried over sodium sulfate. The residue was purified bysilica gel chromatography eluting with a gradient of 0-70% ethyl acetatein hexanes. The fractions containing product were condensed in vacuo toprovide a colorless oil. The oil was dissolved in diethyl ether (25 mL),causing the starting material to solidify from solution. Filtration gavethe title compound as a white solid.

The following compounds were also prepared by methods described inExample 9:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (4-methanesulfonyl-benzyl)-propyl-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-dimethylsulfamoyl-benzylamide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (2-chloro-4-dimethylsulfamoyl-benzyl)-methyl-amide.

Example 10 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 2-chloro-4-cyano-benzylamide (10)

In a sealed tube, 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(4-bromo-2-chloro-benzyl)-methoxymethyl-amide (0.30 g, 0.65 mmol),Pd₂(dba)₃ (40.0 mg, 0.440 mmol), dppf (44 mg, 0.079 mmol), Zn(CN)₂ (77mg, 0.66 mmol), and Zn (10.5 mg, 0.160 mmol) were dissolved in anhydrousDMF (3 mL). The mixture was warmed at 120° C. for 3 hours. The mixturecooled to room temperature, and diluted with saturated aqueous ammoniumchloride (20 mL), extracted with ethyl acetate (20 mL), washed withbrine (30 mL), and dried over sodium sulfate. The crude was purified bysilica gel chromatography eluting with a gradient of 0-70% ethyl acetatein hexanes to afford the title compound as a white powder.

The following compound was also prepared by methods described in Example10:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-cyano-benzylamide.

Example 11 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 4-carbamoyl-2-chloro-benzylamide (11)

To a suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid2-chloro-4-cyano-benzylamide in a 1:1 mixture of EtOH—H₂O (2.0 mL) wasadded KOH (0.018 g, 0.32 mmol) and a 30% solution of H₂O₂ in H₂O (0.13mL, 1.1 mmol). The suspension was sealed and heated briefly to dissolvethe mixture. The resultant solution was stirred at room temperature for16 hours, during which time a solid precipitated. The mixture wasdiluted with H₂O (10 mL) and the solid was collected by filtration anddried to afford the title compound as a white powder.

The following compound was also prepared by methods described in Example11:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-carbamoyl-benzylamide.

Example 12 Synthesis of3-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoicacid (12)

To a solution of3-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoicacid methyl ester (430 mg, 1.0 mmol) in ethanol (15 mL) was added a 2 Nsolution of aqueous sodium hydroxide (3.0 mL, 6.0 mmol). The mixture washeated at 80° C. for 4 hours. The mixture was cooled and concentrated invacuo to remove the ethanol and then added to a solution of 1 N aqueousHCl (30 mL). The white precipitate was collected by filtration and driedto afford the title compound as a white solid.

The following compound was also prepared by methods described in Example12:

-   4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoic    acid.

Example 13 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 3-methylcarbamoyl-benzylamide (13)

To a solution of3-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-benzoicacid (70 mg, 0.2 mmol) in DMF (5 mL) was added Et₃N (0.07 mL, 0.6 mmol)and PyBOP (100 mg, 0.2 mmol). After 15 minutes of stirring at roomtemperature, methylamine hydrochloride (15 mg, 0.22 mmol) was added.After 16 hours, the mixture was diluted with saturated aqueous ammoniumchloride (20 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate (20 mL), brine (20 mL) and dried over sodium sulfate. Thecrude product was purified by silica gel chromatography eluting with agradient of 0-100% ethyl acetate in hexanes. The material from thecolumn was then crystallized from EtOAc/ether/hexanes to afford thetitle compound as a white solid.

The following compounds were also prepared by methods described inExample 13:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-propylcarbamoyl-benzylamide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-ethylcarbamoyl-benzylamide, and-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-(2-methoxy-ethylcarbamoyl)-benzylamide.

Example 14 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 4-(2-hydroxy-ethylsulfamoyl)-benzylamide (14)

To a chilled (−78° C.) solution of1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-(2-methoxy-ethylsulfamoyl)-benzylamide (22 mg, 0.45 mmol) indichloromethane (5 mL) was added in several portions a 1 M solution ofBBr₃ (0.13 mL, 0.13 mmol) in dichloromethane. The mixture was allowed towarm to room temperature. The mixture was quenched with saturatedaqueous sodium bicarbonate and then extracted with ethyl acetate (3×10mL). The combined organic layers were washed with brine (2×5 mL), driedover magnesium sulfate, filtered and concentrated. The material waspurified by silica gel chromatography eluting with a gradient of 0-100%ethyl acetate in hexanes to afford the title compound as a white powder.

Example 15 Synthesis of 3-Bromo-1H-indazole-4-carboxylic acid methylester (15)

To a solution of 1H-indazole-4-carboxylic acid methyl ester (380 mg, 2.2mmol) in DMF (5 mL) was added N-bromosuccinimide (NBS) (976 mg, 4.32mmol) and KOH (485 mg, 8.64 mmol). After 1 hour, the reaction mixturewas diluted with saturated aqueous ammonium chloride (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with saturated aqueous sodium bicarbonate and brine (20 mL),dried over sodium sulfate and concentrated in vacuo to afford the titlecompound as a solid.

3-Bromo-1H-indazole-4-carboxylic acid methyl ester was then subjected tothe reaction conditions described in Example 2, for the synthesis of1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid, to yield3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid. Using themethods described in Example 2,3-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid was used toprovide the following compounds:

-   3-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methanesulfonyl-benzylamide, and-   3-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methylsulfamoyl-benzylamide.

Example 16 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide (16)

1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(2-methoxy-pyridin-4-ylmethyl)-amide (38 mg, 0.10 mmol) and pyridiniumhydrochloride (117 mg, 1.01 mmol) were heated to 125° C. in a sealedtube. After 10 minutes, the mixture was cooled to room temperature anddiluted with ethyl acetate (3 mL) and water (3 mL). The organic layerwas washed with water (3×3 mL) and concentrated at 45° C. under a streamof nitrogen. The residue was dissolved in CH₂Cl₂ (3 mL) and concentrated(repeated 3 times). The solid was triturated with ether (3 mL), filteredand air dried to afford the title compound as a white solid.

The following compound was also prepared by methods described in Example16:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amide.

Example 17 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide (17)

To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylicacid (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide (50 mg, 0.1 mmol) inDMF (1.0 mL) was added K₂CO₃ (45.8 mg, 0.331 mmol) followed byiodomethane (0.017 mL, 0.28 mmol). The mixture was warmed at 60° C. for3 hours. The mixture was diluted with water (10 mL), and a white solidwas obtained by filtration. The solid was washed with water (5×10 mL)and air dried. The resulting solid was purified by silica gelchromatography eluting with a gradient of 0-5% MeOH in CH₂Cl₂ to affordthe title compound as a white solid.

The following compounds were also prepared by methods described inExample 17:

-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amide,-   [4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-2-oxo-2H-pyridin-1-yl]-acetic    acid ethyl ester,-   [5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-2-oxo-2H-pyridin-1-yl]-acetic    acid ethyl ester,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-carbamoylmethyl-6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amide,-   1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid    (1-cyanomethyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-amide, and-   [4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridin-2-yloxy]-acetic    acid ethyl ester.

Example 18 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (6-amino-pyridin-3-ylmethyl)-amide (18)

[5-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (0.200 g, 0.433 mmol) synthesized as described inExample 4, via the acid chloride and tert-butyl[5-(aminomethyl)pyridine-2-yl]carbamate) was treated with a solution of4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 6 hours at roomtemperature. A solid was obtained by filtration, and partitioned betweensaturated aqueous NaHCO₃ (10 mL) and ethyl acetate (10 mL). The organiclayer was separated and the aqueous layer was extracted with ethylacetate (2×10 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. The resulting solid was trituratedwith ethyl acetate (1 mL), filtered and air dried to afford the titlecompound as a white crystalline solid.

Example 19 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (6-acetylamino-pyridin-3-ylmethyl)-amide (19)

A chilled (0° C.) solution of1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) in DMF (1 mL)was treated with 4-dimethylaminopyridine (1 mg, 0.01 mmol), DIEA (0.39mL, 2.2 mmol) and acetic anhydride (0.062 mL, 0.66 mmol). The mixturewas allowed to gradually warm to room temperature. The solution wasdiluted with ethyl acetate (30 mL) and washed with saturated aqueousNH₄Cl (3×10 mL), saturated aqueous NaHCO₃ (20 mL) and brine (20 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography, eluting with agradient of 70-100% ethyl acetate in hexanes to afford the titlecompound as a white solid.

Example 20 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (6-methanesulfonylamino-pyridin-3-ylmethyl)-amide (20)

To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-amino-pyridin-3-ylmethyl)-amide (40.0 mg, 0.111 mmol) indichloromethane (1.0 mL) was added DIEA (0.15 mL, 0.89 mmol). Thesolution was cooled to 0° C., treated with methanesulfonyl chloride(0.021 mL, 0.28 mmol), and gradually allowed to warm to roomtemperature. The solution was diluted CH₂Cl₂ (20 mL) and washed withsaturated aqueous NH₄Cl (3×10 mL), saturated aqueous NaHCO₃ (10 mL) andbrine (10 mL). The organic layer was dried over MgSO₄, filtered andconcentrated. The crude mixture was diluted with THF (0.5 mL) and a 1 Msolution of TBAF in THF (1.0 mL, 1.0 mmol) was added. The solution waswarmed at reflux for 6 hours. The solution was cooled to roomtemperature and quenched with saturated aqueous NH₄Cl (15 mL), dilutedwith ethyl acetate (15 mL), and washed with NaHCO₃ (10 mL) and brine (10mL). The organic layer was dried over MgSO₄, filtered and concentrated.The residue was purified by silica gel chromatography, eluting with agradient of 0-10% MeOH in CH₂Cl₂ to afford the title compound as asolid.

Example 21 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (6-ethynyl-pyridin-3-ylmethyl)-amide (21)

To a mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-bromo-pyridin-3-ylmethyl)-amide (105 mg, 0.247 mmol), trimethylsilylacetylene (0.105 mL, 0.741 mmol), copper(I) iodide (4.7 mg, 0.025 mmol)and Pd(PPh₃)₂Cl₂ (8.7 mg, 0.012 mmol) was added triethylamine (1.0 mL)and anhydrous DMF (0.25 mL). After 16 hours, the mixture was dilutedwith diethyl ether (50 mL) and quenched with saturated aqueous ammoniumchloride (50 mL). The organic layer was washed with saturated aqueousammonium chloride (50 mL) and brine (50 mL), dried over MgSO₄ andconcentrated. The crude solid was purified by silica gel chromatographyeluting with a gradient of 0-50% ethyl acetate in hexanes to afford1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide as a tan solid.1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid(6-trimethylsilanylethynyl-pyridin-3-ylmethyl)-amide (70.0 mg, 0.158mmol) was dissolved in THF (1.0 mL) and treated with a 1 M solution ofTBAF in THF (0.16 mL, 0.16 mmol) at room temperature. The solution wasstirred for 2 hours and then diluted with diethyl ether (10 mL) andquenched with water (10 mL). The aqueous layers were extracted withdiethyl ether (3×5 mL). The combined organic layers were washed withbrine (10 mL), dried over MgSO₄ and concentrated. The crude product waspurified by silica gel chromatography eluting with a gradient of 0-70%ethyl acetate in hexanes to afford the title compound as a white solid.

Example 22 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid (6-methanesulfonylmethyl-pyridin-3-ylmethyl)-amide (22)

To a solution of the5-({[1-(4-fluoro-phenyl)-1H-indazole-4-carbonyl]-amino}-methyl)-pyridine-2-carboxylicacid ethyl ester (40.0 mg, 0.0960 mmol) in THF (3.0 mL) was addedlithium borohydride (12 mg, 0.57 mmol). The mixture was warmed at refluxfor 18 hours. The solution was cooled to room temperature, quenched withwater (5 mL) and diluted with ethyl acetate (5 mL). The organic layerwas separated and the aqueous layer was extracted with ethyl acetate(2×5 mL). The combined organic layers were washed with brine (5 mL),dried over MgSO₄, filtered and concentrated. The residue was purified bysilica gel chromatography eluting with a gradient of 0-10% MeOH inCH₂Cl₂ to afford the alcohol intermediate as an off-white solid.

To a solution of the alcohol (27 mg, 0.071 mmol) in CH₂Cl₂ (2 mL) wasadded DIEA (0.037 mL, 0.21 mmol) and methanesulfonyl chloride (0.07 mL,0.09 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1hour and quenched with saturated aqueous ammonium chloride (2 mL),washed with brine (2 mL), dried over MgSO₄ and concentrated. Theresultant crude mesylate was dissolved in DMSO (1 mL) and treated withsodium methanesulfinate (8.7 mg, 0.086 mmol) at room temperature. Themixture was stirred for 19 hours, and diluted with water (20 mL) andethyl acetate (20 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with water (2×10 mL), saturated aqueous NaHCO₃ (25mL), brine (25 mL), dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography eluting with agradient of 0-10% MeOH in CH₂Cl₂ to afford the title compound as a whitesolid.

Example 23 Synthesis of6-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (23)

A mixture of 6-bromo-4-indazolecarboxylic acid methyl ester (2.0 g, 7.8mmol), copper(I) iodide (0.4 g, 0.2 mmol), potassium carbonate (1.2 g,8.5 mmol) and 4-fluoroiodobenzene (1.8 g, 8.5 mmol) was charged in asealed tube at room temperature. The tube was evacuated and back-filledwith argon, and DMF (10 mL) andrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.20 g, 1.4 mmol) wasadded. The solution was stirred at 120° C. for 3 hours, cooled to roomtemperature, and diluted with water (30 mL) and ethyl acetate (50 mL).The organic layer was separated, washed with brine (10 mL) and driedover sodium sulfate. The solvent was removed in vacuo. The residue waspurified by silica gel chromatography eluting with a gradient of 0-30%ethyl acetate in hexanes to afford6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.

To a stirred solution of6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester(1.7 g, 4.8 mmol) in water (15 mL) and methanol (15 mL) was added asolution of 2 N aqueous sodium hydroxide (10 mL, 20 mmol). The solutionwas warmed at reflux for 1 hour. The reaction mixture was cooled to roomtemperature and acidified with 1 N aqueous HCl (pH=3-4) to afford aprecipitate which was collected by filtration, washed with MeOH and airdried to afford 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylicacid.

To a stirred room temperature solution of6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.25 g, 0.70mmol) in DMF (15 mL) was added PyBOP (0.45 g, 0.90 mmol) andtriethylamine (0.20 g, 1.6 mmol). After 15 minutes,4-aminomethyl-N-methyl-benzenesulfonamide (0.15 g, 0.7 mmol) was added.After 5 hours, the reaction was quenched with water (30 mL), andextracted with ethyl acetate (30 mL). The combined organic layers werewashed with brine (30 mL) and dried over sodium sulfate and concentratedin vacuo. The residue was purified by silica gel chromatography elutingwith a gradient of 30-50% ethyl acetate in hexanes to afford the titlecompound.

The following compound was also prepared by methods described in Example23.

-   6-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-trifluoromethyl-benzylamide, and-   6-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide.

Example 24 Synthesis of6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (24)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.04 g, 0.08 mmol), Pd₂(dba)₃ (0.009 g,0.01 mmol), 1,1-bis(diphenylphosphino)ferrocene (dppf) (0.005 g, 0.01mmol), zinc cyanide (0.01 g, 0.09 mmol) and zinc powder (0.002 g, 0.02mmol) were charged in a sealed tube with anhydrous DMF (3 mL) at roomtemperature. The reaction mixture was heated at 120° C. for 3 hours. Thesolution was cooled to room temperature and diluted with saturatedaqueous ammonium chloride (10 mL) and ethyl acetate (20 mL). The organiclayer was separated and washed with brine (10 mL) and dried over sodiumsulfate. The solvent was removed in vacuo. The residue was purified bysilica gel chromatography eluting with a gradient of 20-70% ethylacetate in hexanes to afford the title compound.

Example 25 Synthesis of1-(4-Fluoro-phenyl)-6-methanesulfonyl-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (25)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.07 g, 0.1 mmol), copper(II) triflate(0.05 g, 0.1 mmol), N,N′-dimethylethylenediamine (0.04 mL, 0.4 mmol),sodium methanesulfinate (0.02 g, 0.2 mmol) was charged in a sealed tubewith DMSO (5 mL). The tube was capped and the solution was degassed withargon for 5 minutes. The mixture was heated in a microwave at 110° C.for 40 minutes and cooled to room temperature. The solution was dilutedwith ethyl acetate (30 mL) and washed with saturated aqueous ammoniumchloride (10 mL), saturated aqueous NaHCO₃ (5 mL) and brine (5 mL) anddried over sodium sulfate. The solvent was removed in vacuo. The residuewas purified by silica gel chromatography eluting with a gradient of20-50% ethyl acetate in hexanes to afford the title compound.

Example 26 Synthesis of1-(4-Fluoro-phenyl)-6-hydroxy-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (26)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.1 g, 0.2 mmol), bis(pinacolato)diboron(0.1 g, 0.4 mmol), PdCl₂(dppf) (0.04 g, 0.05 mmol), potassium acetate(0.05 g, 0.5 mmol) was charged in a sealed tube with anhydrous THF (7mL). The solution was warmed at 80° C. for 16 hours. The reactionmixture was cooled to room temperature and quenched with water (15 mL)and diluted with CH₂Cl₂ (20 mL). The organic layer was separated andwashed with brine (10 mL) and dried over sodium sulfate. The solvent wasremoved in vacuo. The residue was dissolved in THF (10 mL), and asolution of 30% H₂O₂ in water (0.15 mL, 0.5 mmol) and NaOH (0.01 g, 0.3mmol) were added. The mixture was stirred at 10° C. for 3 hours and thenquenched with water (10 mL) and diluted with CH₂Cl₂ (20 mL). The organiclayer was washed with brine (10 mL) and dried over sodium sulfate. Thesolvent was removed in vacuo. The residue was purified by reversed-phaseHPLC, eluting with a gradient of 5-100% CH₃CN in water. The desiredfractions were combined and diluted with saturated aqueous NaHCO₃ (20mL) and ethyl acetate (20 mL). The organic layer was separated, driedover sodium sulfate and concentrated to afford the title compound.

Example 27 Synthesis of1-(4-Fluoro-phenyl)-6-methyl-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (27)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.05 g, 0.1 mmol), methylboronic acid(0.01 g, 0.2 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05mmol) and a solution of 2 N aqueous sodium carbonate (0.1 mL, 0.2 mmol)was added in a sealed tube with DMF (5 mL). The tube was capped and theresulting solution was degassed with argon for 5 minutes. The reactionwas heated to 120° C. by microwave irradiation for 2.5 hours. Thereaction was cooled to room temperature and quenched with saturatedaqueous ammonium chloride (5 mL) and diluted with ethyl acetate (20 mL).The organic layer was separated, washed with brine (10 mL) and driedover sodium sulfate and concentrated. The residue was purified by silicagel chromatography eluting with a gradient of 20-50% ethyl acetate inhexanes to afford the title compound.

Example 28 Synthesis of1-(4-Fluoro-phenyl)-6-methylamino-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (28)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.05 g, 0.1 mmol), methylaminehydrochloride (0.01 g, 0.2 mmol), palladium(II) acetatedi-t-butylbiphenylphosphine (0.005 g, 0.01 mmol) and sodium t-butoxide(0.03 g, 0.25 mmol) was charged in a sealed tube with dioxane (5 mL).The tube was capped, degassed with argon for 5 minutes and warmed at 90°C. for 2 hours. The reaction was cooled to room temperature and filteredthrough diatomaceous earth, and diluted with water (5 mL) and ethylacetate (20 mL). The organic layer was separated and washed with brine(10 mL), dried over sodium sulfate, and concentrated. The residue waspurified by reversed-phase HPLC eluting with a gradient of 5-100% CH₃CNin water. The desired fractions were combined and diluted with saturatedaqueous NaHCO₃ (20 mL) and ethyl acetate (20 mL). The organic layer wasseparated, dried over sodium sulfate and concentrated to afford thetitle compound.

The following compounds were also prepared by methods described inExample 28:

-   1-(4-Fluoro-phenyl)-6-[(2-methoxy-ethyl)-methyl-amino]-1H-indazole-4-carboxylic    acid 4-methylsulfamoyl-benzylamide,-   6-Dimethylamino-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-methylsulfamoyl-benzylamide, and-   6-(2-Dimethylamino-ethylamino)-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic    acid 4-methylsulfamoyl-benzylamide.

Example 29 Synthesis of1-(4-Fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylicacid ethyl ester (29)

A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-methylsulfamoyl-benzylamide (0.2 g, 0.4 mmol), triethylamine (0.1 g,0.9 mmol), dichlorobis(benzonitrile)palladium (0.02 g, 0.05 mmol) and1,1-bis(diphenylphosphino)ferrocene (0.03 g, 0.05 mmol) was charged in asealed tube with absolute ethanol (15 mL). The solution was placed under15 bars of carbon monoxide and warmed at 140° C. for 4 hours. Themixture was cooled to room temperature and returned to atmosphericpressure. The reaction was diluted with water (30 mL) and the solid wascollected by filtration. The filtrate was diluted with water (20 mL) andethyl acetate (20 mL). The organic layer was separated and washed withbrine (10 mL) and dried over sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography eluting with agradient of 30-70% ethyl acetate in hexanes to afford the titlecompound.

Example 30 Synthesis of1-(4-Fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylicacid (30)

To a stirred solution of1-(4-fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylicacid ethyl ester (0.13 g, 0.26 mmol) in H₂O (10 mL) and EtOH (20 mL) wasadded a 2 N solution of aqueous KOH (10 mL, 20 mmol). The mixture waswarmed at reflux for 1 hour and cooled to room temperature. The mixturewas acidified with 2 N aqueous HCl (pH=3-4) and diluted with ethylacetate (30 mL). The organic layer was separated and washed with brine(20 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was triturated with diethyl ether (10 mL) to afford the titlecompound.

Example 31 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4,6-dicarboxylicacid 6-methylamide 4-(4-methylsulfamoyl-benzylamide) (31)

To a stirred solution of1-(4-fluoro-phenyl)-4-(4-methylsulfamoyl-benzylcarbamoyl)-1H-indazole-6-carboxylicacid (0.04 g, 0.1 mmol) in DMF (20 mL) was added PyBOP (0.05 g, 0.2mmol) and TEA (0.03 g, 0.2 mmol) at room temperature. The resultingsolution was stirred for 15 minutes and then methylamine hydrochloride(0.007 g, 0.2 mmol) was added. The reaction was stirred for 5 hours anddiluted with water (20 mL) and ethyl acetate (30 mL). The organic layerwas separated and washed with brine (10 mL), dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gelchromatography eluting with a gradient of 30-50% ethyl acetate inhexanes afford the title compound.

The following compound was also prepared by methods described in Example31:

-   1-(4-Fluoro-phenyl)-1H-indazole-4,6-dicarboxylic acid    6-[(2-hydroxy-ethyl)-amide]-4-(4-methylsulfamoyl-benzylamide).

Example 32 Synthesis of6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid4-(1-methyl-piperidin-4-ylsulfamoyl)-benzylamide (32)

A sealed tube was charged with6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester(1.5 g, 4.3 mmol), Pd₂(dba)₃ (0.4 g, 0.4 mmol), zinc cyanide (0.6 g, 5mmol), dppf (0.3 g, 0.4 mmol) and zinc powder (0.2 g, 3 mmol) and DMF(20 mL). The reaction solution was degassed with argon for 15 minutesand warmed at 120° C. for 3 hours. The reaction was cooled to roomtemperature, diluted with saturated aqueous ammonium chloride (10 mL)and ethyl acetate (50 mL). The organic layer was separated and washedwith brine (10 mL), dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with a gradient of 0-20% ethyl acetate in hexanes to afford6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.

To a stirred solution of6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester(0.30 g, 1.1 mmol) in water (10 mL) and methanol (10 mL) was added a 2 Naqueous sodium hydroxide (10 mL, 20 mmol). The mixture was warmed atreflux for 1 hour, cooled to room temperature, and acidified with 1 Naqueous HCl (pH=3-4). The white solid was collected by filtration,washed with MeOH (10 mL) and dried to afford6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.

To a stirred solution of6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.040 g, 0.14mmol) in DMF (15 mL) was added PyBOP (0.1 g, 0.2 mmol) and triethylamine(0.04 g, 0.3 mmol) at room temperature. After 15 minutes,4-aminomethyl-N-(1-methyl-piperidin-4-yl)-benzenesulfonamide (0.05 g,0.16 mmol) was added. After 5 hours, the mixture was diluted with water(30 mL) and ethyl acetate (30 mL). The organic layer separated andwashed with brine (20 mL), dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with a gradient of 30-50% ethyl acetate in hexanes to afford thetitle compound.

The following compounds were also prepared by methods described inExample 32:

-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    3-methanesulfonyl-benzylamide,-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-bromo-pyridin-3-ylmethyl)-amide,-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-methanesulfonyl-pyridin-3-ylmethyl)-amide,-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    (6-methanesulfonylamino-pyridin-3-ylmethyl)-amide,-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-(4-methyl-piperazine-1-sulfonyl)-benzylamide, and-   6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid    4-[methyl-(1-methyl-piperidin-4-yl)-sulfamoyl]-benzylamide.

Example 33 Synthesis of 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide (33)

To a chilled (0° C.) solution of 6-bromo-pyridine-3-carboxaldehyde (15.0g, 80.6 mmol) in a 1:1 mixture of ether-toluene (400 mL) was added a 2 Msolution of ethyl magnesium chloride (40.0 mL, 80.0 mmol) in THF over a15 minute period. The solution was stirred for 4 hours, and a more polarproduct was observed by TLC (ethyl acetate-hexanes 3:7). The mixture wasdiluted with saturated aqueous ammonium chloride (300 mL) and theorganic phase separated. The aqueous layer was extracted with ethylacetate (2×100 mL). The combined organic layers were washed with brine(2×50 mL), dried over magnesium sulfate, filtered and concentrated. Thecrude material was passed through a pad of silica gel eluting 0-100%dichloromethane in hexanes. The material from the pad was purified bysilica gel chromatography eluting with a gradient of 2-15% ethyl acetatein hexanes to afford 1-(6-bromo-pyridin-3-yl)-propan-1-ol.

To a solution of 1-(6-bromo-pyridin-3-yl)-propan-1-ol (12.95 g, 59.93mmol) in THF (200 mL) was added activated MnO₂ (6.4 g, 63 mmol). Themixture was stirred at room temperature overnight. The reaction wasmonitored by TLC (ethyl acetate-hexanes 4:6) indicating startingmaterial and a new less polar product. To the mixture was addedadditional MnO₂ (6.0 g, 59 mmol) and the mixture stirred over theweekend. The reaction was monitored by TLC (ethyl acetate-hexanes 3:7)indicting starting material was still present. The mixture was warmed atreflux for 6 hours. Starting material was still evident by TLC. Themixture was filtered through diatomaceous earth and concentrated. Theresulting solid was triturated with diethylether to afford 4 grams ofwhite solid. The filtrate was concentrated dissolved in dichloromethaneand combined with the 4 grams of solid and the Dess-Martin periodinane(19 g, 44.8 mmol) was added. The mixture was stirred for 1 hour and wasthen diluted with saturated aqueous potassium carbonate (200 mL) andconcentrated. The resulting solid was collected by filtration, washedwith water and dried in the funnel by pulling vacuum overnight. Thesolid was then suspended in dichloromethane and filtered. The filtratewas collected and passed through a pad of silica gel eluting withdiethylether to afford 1-(6-bromo-pyridin-3-yl)-propan-1-one.

A mixture of 1-(6-bromo-pyridin-3-yl)-propan-1-one (11.8 g, 55.1 mmol),(R)-(+)-2-methyl-2-propanesulfinamide (8.0 g, 66 mmol) and titaniumisopropoxide (18.0 mL, 61.4 mmol) in dichloroethane (65 mL) was warmedat reflux for 2 days. The reaction was monitored by TLC (ethylacetate-hexanes 2:8) indicating a new more polar product than startingketone, however ketone was still evident. The mixture was diluted withfirst dichloromethane (600 mL) and then water (15 mL) was added. Themixture was stirred for 10 minutes and then magnesium sulfate added. Themixture was filtered through diatomaceous earth and concentrated. Theresidue was purified by silica gel chromatography eluting with agradient of 0-40% ethyl acetate in hexanes and then a gradient of 0-40%ethyl acetate in dichloromethane to afford 2-methyl-propane-2-sulfinicacid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide.

To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid[1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide (10.4 g, 32.8 mmol) inTHF (150 mL) was added a 1 N solution of lithiumtri-sec-butylborohydride (L-Selectride) (33.0 mL, 33.0 mmol) in THF. Thereaction was monitored by TLC (ethyl acetate-ether 3:7) indicating asingle diastereomer when compared to a mixture of diastereomers preparedby reduction with lithium borohydride in THF. After 6 hours, the mixturewas quenched with saturated aqueous ammonium chloride (100 mL) andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with saturated aqueous ammonium chloride (2×50 mL), brine(50 mL), dried over magnesium sulfate, filtered and concentrated. Thecrude material was purified by silica gel chromatography eluting with agradient of 0-20% diethylether in dichloromethane to afford 7.5 g ofmaterial which was triturated with diethylether to afford in two crops2-methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide which was consistent with asingle diastereomer by ¹H NMR. This material and the filtrate werepurified separately by silica gel chromatography using a gradient of0-40% ethyl acetate in dichloromethane. The material from the columnswas recrystallized from dichloromethane-hexanes-ether to afford in 3crops 2-methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide which was consistent with asingle diastereomer.

To a solution of 2-methyl-propane-2-sulfinic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide (5.35 g, 16.8 mmol) inmethanol (25 mL) was added a solution of 4 N HCl in dioxane (10.0 mL,40.0 mmol). The mixture was monitored by TLC for the disappearance ofstarting material (ethyl acetate-hexanes 3:7). After 2 hours, themixture was concentrated to near dryness to afford a white solid whichwas diluted with diethylether and collected by filtration to afford(S)-1-(6-bromo-pyridin-3-yl)-propylamine hydrochloride.

A suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (258mg, 1.00 mmol) was heated at reflux in thionyl chloride (5 mL) until thesolid dissolved. After 45 minutes, the mixture was concentrated todryness. The yellow residue was diluted with dichloromethane and(S)-1-(6-bromo-pyridin-3-yl)-propylamine hydrochloride (288 mg, 1.00mmol) was added followed by triethylamine (1.0 mL, 7.2 mmol). After 30minutes, the reaction was diluted with saturated aqueous ammoniumchloride (10 mL) and extracted with ethyl acetate (4×10 mL). Thecombined organic layers were washed with brine (3×10 mL), dried overmagnesium sulfate, filtered and concentrated. The crude material wasdiluted with dichloromethane and purified by silica gel chromatographyeluting with a gradient of 0-100% ethyl acetate in hexanes. The materialfrom the column was triturated with ether to afford1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide.

1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide was converted to1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid[(S)-1-(6-methanesulfonyl-pyridin-3-yl)-propyl]-amide as described inExample 7.

Example 34 Synthesis of6-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid[(S)-1-(6-methanesulfonyl-pyridin-3-yl)-propyl]-amide (34) and1-(4-Fluoro-phenyl)-6-methanesulfonyl-1H-indazole-4-carboxylic acid[(S)-1-(6-methanesulfonyl-pyridin-3-yl)-propyl]-amide (35)

A microwave tube was charged with6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid[(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide (90.0 mg, 0.170 mmol,prepared as described in Example 23), copper (I) iodide (143 mg, 0.75mmol) and sodium methanesulfinate (77.0 mg, 0.75 mmol) in DMSO (20 mL).The tube was capped and the solution was degassed with argon for 3minutes. The mixture was warmed in the microwave at 130° C. After 40minutes, the reaction was diluted with saturated aqueous ammoniumchloride (100 mL), saturated aqueous sodium bicarbonate (50 mL) andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate and concentrated in vacuo. Thecrude mixture was purified via reversed-phase HPLC to afford the titlecompounds.

Assessment of Biological Properties

Compounds are assessed for the ability to block the interaction of CCR1and its ligand in a functional cellular assay measuring calcium flux inresponse to MIP-1α in CCR1-transfected cells.

Method A: Non-adherent cells purchased from Chemicon Corporation(HTS005C), stably expressing recombinant CCR1 and G-alpha-16 are grownin RPMI 1640 medium (Mediatech 10-080-CM) supplemented with 10%heat-inactivated FBS, 0.4 mg/mL Geneticin and penicillin/streptomycin.On the day of the assay, the cells are transferred to a beaker anddye-loaded in bulk using a Fluo-4 NW Calcium Assay Kit with probenecid(Invitrogen F36205) at 0.8E6 cells/mL for 1 hour at room temperature.After 1 hour, they are seeded in a 384-well tissue culture-treated plateat a density of 20,000 cells/well. Appropriately diluted test compoundis added to the well to achieve a top concentration of 3,000 nM (diluted3-fold with 10 doses total). The final concentration of DMSO is 1%. Thebuffer is HBSS (Invitrogen 14025) with 20 mM HEPES at pH 7.4. The cellsare allowed to incubate 1 hour in the dark at room temperature. Theplates are transferred to the FLIPR TETRA where MIP-1 alpha in 1% BSA isadded at the EC80 final concentration. Wells +/−MIP-1 alpha containingdiluted DMSO instead of compound serve as the controls. Intracellularcalcium flux is recorded on the FLIPR TETRA, using excitation at 470/495nm and emission at 515/575 nm Data are analyzed using Activity Basesoftware.

Method B: Non-adherent cells purchased from Chemicon Corporation(HTS005C), stably expressing recombinant CCR1 and G-alpha-16 are grownin RPMI 1640 medium (Mediatech 10-080-CM) supplemented with 10% FBS, 0.4mg/mL Geneticin and penicillin/streptomycin. On the day of the assay,the cells are loaded with Calcium 4 dye (Molecular Devices R7448) withProbenecid (Invitrogen P346400) at 8E5 cells/mL for 1 hour at roomtemperature. After 1 hour, they are seeded in a 384-well tissueculture-treated plate at a density of 20,000 cells/well. Appropriatelydiluted test compound is added to the well to achieve a topconcentration of 3,000 nM (diluted 4-fold with 10 doses total). Thefinal concentration of DMSO is 1%. The buffer is HBSS (Invitrogen 14025)with 20 mM HEPES at pH 7.4. The cells incubate 30 minutes at 37 C andthen 30 minutes at room temperature. The plates are transferred to theHAMAMATSU FDSS6000 where MIP-1 alpha in 1% BSA is added at the EC80final concentration. All plates must be read within 4 hours of the startof dye-loading. Wells +/−MIP-1alpha containing diluted DMSO instead ofcompound serve as the controls. Data are analyzed using Activity Basesoftware.

In general, the preferred potency range (IC₅₀) of compounds in the aboveassays is between 0.1 nM to 10 μM, the more preferred potency range is0.1 nM to 1 μM, and the most preferred potency range is 0.1 nM to 100nM.

Representative compounds of the invention have been tested in the aboveassay and have shown activity as CCR1 antagonists.

TABLE II (Method A) Method A Name IC₅₀ (nM)1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 3,5- 25dimethoxy-benzylamide 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid4- 68 methanesulfonyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 3- 76bromo-benzylamide 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 3-61 methanesulfonyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 2- 4.0chloro-4-methylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid [(S)- 191-(3-bromo-phenyl)-butyl]-amide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid [1-(3- 14trifluoromethyl-phenyl)-ethyl]-amide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 2- 6.7chloro-4-methanesulfonyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 3- 22trifluoromethyl-benzylamide,1-(6-Fluoro-pyridin-3-yl)-1H-indazole-4-carboxylic acid 173-trifluoromethyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (2- 22methoxy-pyridin-4-ylmethyl)-amide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 2- 5.4fluoro-4-methylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (2- 120cyano-pyridin-4-ylmethyl)-amide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 4.5methylsulfamoyl-benzylamide 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 4- 14 (morpholine-4-sulfonyl)-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 5.6dimethylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 5.5isopropylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(2- 10methoxy-ethylsulfamoyl)-benzylamide1-(4-Fluoro-phenyl)-6-methanesulfonyl-1H-indazole-4- 28 carboxylic acid4-methylsulfamoyl-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 0.3 acid4-methylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-6-methyl-1H-indazole-4-carboxylic 20 acid4-methylsulfamoyl-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 55(isopropylsulfamoyl-methyl)-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(2- 9.2hydroxy-ethylsulfamoyl)-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(2- 110acetylamino-ethylsulfamoyl)-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(4- 12methyl-piperazine-1-sulfonyl)-benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 20(tetrahydro-pyran-4-ylsulfamoyl)-benzylamide[4-({[1-(4-Fluoro-phenyl)-1H-indazole-4-carbonyl]- 140amino}-methyl)-pyridin-2-yloxy]-acetic acid ethyl ester1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4- 44[methyl-(1-methyl-piperidin-4-yl)-sulfamoyl]- benzylamide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-(4- 23dimethylamino-piperidine-1-sulfonyl)-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 2.0 acid3-methanesulfonyl-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 21 acid(6-bromo-pyridin-3-ylmethyl)-amide1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid 3- 55methylsulfamoyl-benzylamide 1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylicacid 3- 45 dimethylsulfamoyl-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 7.1 acid(6-methanesulfonyl-pyridin-3-ylmethyl)-amide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 1.5 acid4-(4-methyl-piperazine-1-sulfonyl)-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 4.4 acid(6-methanesulfonylamino-pyridin-3-ylmethyl)- amide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 18 acid4-(1-methyl-piperidin-4-ylsulfamoyl)-benzylamide6-Cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 5.1 acid4-[methyl-(1-methyl-piperidin-4-yl)-sulfamoyl]- benzylamide

TABLE III (Method B) Method B Name IC₅₀ (nM)1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid [(S)-1-  2(6-methanesulfonyl-pyridin-3-yl)-propyl]-amide6-Bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic 23 acid[(S)-1-(6-methanesulfonyl-pyridin-3-yl)-propyl]-amideMethod of Use

The compounds of the invention are effective antagonists of theinteractions between CCR1 and its chemokine ligands and thus inhibitCCR1-mediated activity. Therefore, in one embodiment of the invention,there is provided methods of treating autoimmune disorders usingcompounds of the invention. In another embodiment, there is providedmethods of treating inflammatory disorders using compounds of theinvention.

Without wishing to be bound by theory, by antagonizing the interactionsbetween CCR1 and its chemokine ligands, the compounds block chemotaxisof pro-inflammatory cells including monocytes, macrophages dendriticcells, eosinophils, and T cells (TH1) cells and other CCR1 positivecells to inflamed tissues and thereby ameliorate the chronicinflammation associated with autoimmune diseases. Thus, the inhibitionof CCR1 activity is an attractive means for preventing and treating avariety of autoimmune disorders, including inflammatory diseases,autoimmune diseases, organ (Horuk et al. (2001) JBC 276 p. 4199) andbone marrow transplant rejection and other disorders associated with aninflux of pro-inflammatory cells. For example, the compounds of theinvention may be used to prevent or treat acute or chronic inflammation,allergies, contact dermatitis, psoriasis, rheumatoid arthritis, multiplesclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, graft versus host disease(and other forms of organ or bone marrow transplant rejection),Alzheimer's disease (Halks-Miller et al. (2003) Ann Neurol 54 p. 638),Asthma (Jouber et al. (2008) J. Immun 180 p. 1268) chronic kidneydisease (Topham et al. (1999) J. Clin. Invest. 104 p. 1549), sepsis (Heet al. (2007) Am J. Physio 292 p. G1173), autoimmune myocarditis(Futamats et al. (2006) J Mol Cell Cardiology 40 p. 853) and systemiclupus erythematosus. In particular, the compounds may be used to preventor treat rheumatoid arthritis and multiple sclerosis. Other disordersassociated with the trafficking of pro-inflammatory cells will beevident to those of ordinary skill in the art and can also be treatedwith the compounds and compositions of this invention.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased antagonist activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

1. A compound of the formula (I)

wherein Ar₁ is heteroaryl or heterocycle each optionally substituted byone to three R_(a); X₁ is a —(CH₂)_(n)— wherein one or more hydrogenatoms can be replaced by R_(a); X₂ is Ar₂, —S(O)_(m)—Ar₂ or—S(O)_(m)NR_(e)R_(f) or —S(O)_(m)NH—Ar₂; Ar₂ is carbocycle, heteroarylor heterocycle each optionally substituted by one to three R_(b); R₁ ishydrogen, C₁₋₆ alkyl or C₁₋₆alkoxyC₁₋₆alkyl; R₂, R₃ are eachindependently hydrogen or C₁₋₆ alkyl optionally substituted by R_(a);R_(a) is C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkoxycarbonyl, amino, mono- or di-C₁₋₆ alkylamino,C₃₋₆ cycloalkylamino, C₁₋₆ alkylaminocarbonyl, C₁₋₆ acyl, C₁₋₆acylamino, C₁₋₆ dialkylaminocarbonyl, hydroxyl, halogen, cyano, nitro,oxo, R₄—S(O)_(m)—NH—, R₄—NH—S(O)_(m)—, aryl or carboxyl; R_(b) ishydroxyl, carboxyl, halogen, —(CH₂)_(n)—CN, nitro, oxo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, —(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—,R₄—S(O)_(m)—NR_(e)—, R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), heterocyclyl, aryl or heteroaryl,each substituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, aryl or carboxyl; each R_(c), R_(d) are independentlyhydrogen, C₁₋₆ alkyl, C₁₋₆ acyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy,hydroxyC₁₋₆ alkyl, C₁₋₆ alkylC₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, C₁₋₆alkoxycarbonyl or —(CH₂)_(n)—NR_(e)R_(f); each R_(e), R_(f) areindependently hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy,hydroxyC₁₋₆ alkyl or C₁₋₆ acyl; R₄ is hydrogen, C₁₋₆ alkyl,heterocyclyl, aryl or heteroaryl each optionally substituted with C₁₋₆alkyl, C₁₋₆ alkoxy, halogen, hydroxyl, amino, mono- or di-C₁₋₆alkylamino, C₁₋₆ alkoxycarbonyl or C₁₋₆ acylamino; R₅ is hydrogen orR_(a); R_(x) is hydrogen or halogen; each n, x are independently 0-3;each m is independently 0-2; or a pharmaceutically acceptable saltthereof.
 2. The compound to claim 1 and wherein Ar_(i) is thienyl,furanyl, pyranyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl,imidazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinylor triazinyl each optionally substituted by one to three R_(a); X₁ is a—(CH₂)_(n)—; Ar₂ is aryl, furanyl, pyranyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzimidazolonyl, tetrahydropyranyl,dioxanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl,pyrrolyl, imidazolyl, thienyl, thiadiazolyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl, pyridinonyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl,piperidinyl, piperazinyl, purinyl, quinolinyl, dihydro-2H-quinolinyl,isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl,indolyl, isoindolyl, benzofuranyl, benzopyranyl or benzodioxolyl eachoptionally substituted by one to three R_(b); R₁ is hydrogen or C₁₋₄alkyl; R₂, R₃ are each independently hydrogen or C₁₋₃ alkyl; R_(a) isC₁₋₅ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, amino,C₁₋₅ acyl, C₁₋₅ acylamino, halogen, cyano, nitro, hydroxyl, C₁₋₅alkyl-S(O)_(m)—NH—, C₁₋₅ alkyl-NH—S(O)_(m)— or carboxyl; R_(b) ishydroxyl, carboxyl, halogen, cyano, —CH₂—CN, C₁₋₅ alkyl, C₂₋₅ alkynyl,C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,—(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—, R₄—S(O)_(m)—NR_(e)—,R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), phenyl, pyrazolyl, pyrrolyl,imidazolyl, thiadiazolyl, pyridinyl, pyridinonyl, pyrimidinyl,pyridazinyl, pyrazinyl, pyrrolidinyl, piperidinyl or piperazinyl, eachsubstituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, phenyl, naphthyl or carboxyl; R₄ is hydrogen, C₁₋₅alkyl, phenyl, naphthyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl,pyrrolyl, imidazolyl, thienyl, thiadiazolyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl, pyridinonyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl,piperidinyl, piperazinyl or tetrahydropyranyl, each optionallysubstituted with halogen, hydroxyl, C₁₋₅alkyl, C₁₋₅ alkoxy, amino, mono-or di-C₁₋₅ alkylamino, C₁₋₅ alkoxycarbonyl or C₁₋₅ acylamino; R_(x) ishydrogen.
 3. The compound to claim 2 and wherein Ar₁ is thienyl,furanyl, pyranyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl each optionallysubstituted by one to three R_(a); Ar₂ is phenyl, naphthyl,benzimidazolyl, benzimidazolonyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl, pyridinonyl,pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl,isoindolyl, benzofuranyl or benzopyranyl each optionally substituted byone to three R_(b); R₁ is hydrogen or C₁₋₃ alkyl; R₂, R₃ are eachindependently hydrogen or C₁₋₃ alkyl; R_(a) is C₁₋₅ alkyl, C₃₋₆cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl, halogen, cyano, hydroxyl,C₁₋₅ alkyl-S(O)_(m)—NH—, C₁₋₅ alkyl-NH—S(O)_(m)— or carboxyl; R_(b) ishydroxyl, carboxyl, halogen, cyano, —CH₂—CN, C₁₋₅ alkyl, C₂₋₄ alkynyl,C₃₋₇ cycloalkyl, C₁₋₅ alkoxy, C₁₋₅ alkoxycarbonyl,—(CH₂)_(n)—NR_(c)R_(d), R₄—S(O)_(m)—, R₄—S(O)_(m)—NR_(e)—,R₄—NR_(e)—S(O)_(m)—, —NR_(f)—C(O)—R_(e),—(CH₂)_(x)—C(O)—(CH₂)_(n)—NR_(c)R_(d), phenyl, pyrazolyl, pyrrolyl,imidazolyl, thiadiazolyl, pyridinyl, pyridinonyl, pyrimidinyl,pyridazinyl, pyrazinyl, pyrrolidinyl, piperidinyl or piperazinyl, eachsubstituent on R_(b) where possible is optionally halogenated orsubstituted with 1 to 3 C₁₋₆ alkyl, C₁₋₆ acyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkyl-S(O)_(m)—, phenyl, naphthyl or carboxyl; each R_(c), R_(d) areindependently hydrogen, C₁₋₆ alkyl, C₁₋₆ acyl, C₃₋₁₀ cycloalkyl, C₁₋₆alkoxy, hydroxyC₁₋₆ alkyl, C₁₋₆ alkylC₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl,C₁₋₆ alkoxycarbonyl or —(CH₂)_(n)—NR_(e)R_(f); each R_(e), R_(f) areindependently hydrogen, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆ alkoxy,hydroxyC₁₋₆ alkyl or C₁₋₆ acyl; R₄ is hydrogen, C₁₋₅ alkyl, phenyl,naphthyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyrrolyl,imidazolyl, thienyl, thiadiazolyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholinyl, morpholinyl, pyridinyl, pyridinonyl,pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolidinyl,piperidinyl or piperazinyl, each optionally substituted with halogen,hydroxyl, C₁₋₅ alkoxy, amino, mono- or di-C₁₋₅ alkylamino, C₁₋₅alkoxycarbonyl or C₁₋₅ acylamino; R₅ is hydrogen, CN, methyl,—S(O)₂—CH₃.
 4. The compound to claim 2 and wherein Ar₁ is thienyl,furanyl, pyranyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl each optionallysubstituted by one to three R_(a); X₁ is a —(CH₂)_(n)—; X₂ is Ar₂; Ar₂is phenyl, naphthyl, benzimidazolyl, benzimidazolonyl, morpholinyl,pyridinyl or pyridinonyl, each optionally substituted by one to twoR_(b); R₁ is hydrogen or C₁₋₃ alkyl; R₂, R₃ are each independentlyhydrogen or C₁₋₃ alkyl; R_(a) is C₁₋₅ alkyl, C₃₋₆ cycloalkyl, C₁₋₅alkoxy, C₁₋₅ alkoxycarbonyl, halogen, cyano, hydroxyl, C₁₋₅alkyl-S(O)_(m)—NH—, C₁₋₅ alkyl-NH—S(O)_(m)— or carboxyl; R_(b) iscarboxyl, halogen, cyano, —CH₂—CN, C₁₋₄ alkyl, CF₃, C₁₋₄ alkoxy, C₁₋₄alkoxycarbonyl, ethynyl, phenyl, imidazolyl, piperidinyl, piperazinyl,or R_(b) is NH₂—S(O)₂—, NH₂—C(O)—CH₂—, —N(C₁₋₃ alkyl)₂, —N(C₁₋₃alkyl)C(O)—C₁₋₃ alkyl, —C(O)NH—C₁₋₃ alkyl, —C(O)N(C₁₋₃ alkyl)₂,—C(O)NH—(CH₂)₁₋₂—O—C₁₋₃alkyl, —C(O)NH₂, —S(O)₂—C₁₋₃ alkyl,—S(O)₂—(CH₂)₁₋₂—C(O)—O—C₁₋₃alkyl, —S(O)₂—NH—C₁₋₃ alkyl, S(O)₂—N(C₁₋₃alkyl)₂, —CH₂—S(O)₂—N(C₁₋₃ alkyl)₂, —S(O)₂NH—(CH₂)₁₋₂—O—C₁₋₃alkyl,—S(O)₂NH—(CH₂)₁₋₂—N(C₁₋₃alkyl)₂, —S(O)₂NH—(CH₂)₁₋₂—OH,—S(O)₂NH—(CH₂)₁₋₂—NHC(O)C₁₋₃alkyl), —S(O)₂NH-(tetrahydropyran-4-yl),—S(O)₂NR_(e)(1-C₁₋₃alkylpiperidin-4-yl),—S(O)₂NH-(4-C₁₋₃alkylpiperazin-1-yl),—S(O)₂NH-(4-diC₁₋₃alkylaminopiperidin-4-yl), —S(O)₂-morpholinyl,—C(O)—O—C₁₋₃ alkyl, —CH₂—C(O)—O—C₁₋₃ alkyl, —SCF₃ or —SCH₃.
 5. Thecompound to claim 4 and wherein Ar₁ is

and the combination of

is


6. A compound chosen from

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to claim 1.